Bis(amidinohydrazones) of steroidal diones

ABSTRACT

THE DISCLOSURE IS DIRECTED TO BIS(AMIDINOHYDRAZONES) OF GONA-3,17-DINORPREGNA-3,20-DIONES. THE COMPOUNDS HAVE DARDIOTONIC ACTIVITY.

United States Patent 3,644,436 BIS(AMIDINOHYDRAZONES) 0F STEROIDAL DIONES Gerhard R. Wendt, Havertown, Kurt W. Ledig, Philadelphia, and Daniel M. Teller, King of Prussia, Pa., assignors to American Home Products Corporation, New York, N.Y.

No Drawing. Continuation-impart of application Ser. No. 594,390, Nov. 15, 1966. This application Apr. 30, 1969, Ser. No. 820,646

Int. Cl. C07c 169/00 s. or. 260-397 8 Claims ABSTRACT OF THE DISCLOSURE The disclosure is directed to bis(amidinohydrazones) of gona-3,17-diones and 18,19-dinorpregna-3,20-diones. The compounds have cardiotonic activity.

This application is a continuation-in-part of application Ser. No. 594,390, filed Nov. 15, 1966, now abandoned.

This invention relates to and has for its objects the provision of new physiologically active compounds. More particularly, this invention relates to the production of compounds of the formula:

and the pharmaceutically acceptable acid-addition salts thereof, wherein the 4,5-, 6,7- or 9,10-positions are saturated or unsaturated; R is an alkyl group of 2 to 8 carbon atoms (e.g., ethyl, propyl, butyl, etc.); R is selected from the group consisting of hydrogen, alkyl of less than carbon atoms, hydroxy and lower alkoxy; R is selected from the group consisting of hydrogen and methyl; and Z is selected from the group consisting of wherein R is selected from the group consisting of hydrogen and hydroxy, with the proviso that R is hydroxy or lower alkoxy only when Z is In a particularly advantageous embodiment of the present invention when the 4,5-position is unsaturated, either the 6,7- or 9,10-position is also unsaturated.

Among the suitable acid-addition salts include, inter alia, inorganic acids, such as the hydrohalic acids (e.g., hydrochloric and hydrobromic acid), sulphuric acid, nitric acid, boric acid and phosphoric acid, and organic acids such as oxalic, fumaric, tartaric, citric, acetic, succinic and maleic acid.

The compounds of this invention can be prepared by interacting compounds of the formulae:

Patented Feb. 22, 1972 "ice wherein the 4,5-, 6,7- or 9,10-p0sitions are saturated or unsaturated; R R and R are as hereinbefore described with an aminoguanidine salt according to the process described in German Patent No. 1,175,228, to yield the corresponding amidinohydrazone derivatives.

With the 3,17-diketo compounds, the reaction initially takes place in the 3-position, consequently, if desired, the B-amidinohydrazone derivative may be isolated. The 3- amidinohydrazone compound has been found to be less soluble than the corresponding bis(amidinohydrazone) derivative so that a reduction in the volume of the solvent during the reaction has been found to cause the 3 amidinohydrazone compound to precipitate out of so lution and be recovered in high yields.

Some of the suitable starting steroids are commercially available or can be prepared by conventional methods.

Starting materials for 13-ethylgon-4-ene-3,l7-dione, bis- (amidinohydrazone) are known in the prior art, for instance, Belgium Pat. 608,370.

Starting materials for 13-(lower)alkylgona-4,9-diene- 3,17-dione, bis(amidinohydrazone) are known in the prior art, for instance, Smith et al., J. Chem. Soc. 4472 (1964).

Starting materials for compounds typified by 13-ethyl- 18,19-dinorpregn 4 ene-3,20-dione, bis(amidinohydra zone) may be prepared from the appropriate Smith et al. compounds by following the procedure described in Mills et al., J.A.C.S. 80, 6118 (1958).

Starting materials for compounds typified by l3-ethyl- Su-gonane 3,17 dione, bis(amidinohydrazone) are disclosed in copending patent application Serial No. 337,432, filed Mar. 25, 1966, now abandoned.

Starting materials for compounds typified by 13-ethylgona-4,6-diene-3,-17-dione, bis(amidinohydrazone) may be prepared by the following procedure. To a stirred suspension of 2.7 g. of dl 13-ethylgona-4,6-dien-17/3-01-3- one ['Buzby et al. 1., Med. Chem., 9, 782 (1956)], 3.24 g. of anhydrous magnesium sulfate, and 108 ml. of acetone is added, 4.05 ml. of Jones reagent [C. Djerassi, R. R. Engle and A. Browers, J. Org. Chem., 21, 1547 (1956)]. After 3 minutes 13.5 ml. of isopropyl alcohol is added and the reaction mixture diluted with water. After extracting the material with chloroform, the solution is washed with sodium bicarbonate. The residue obtained upon evaporation of the solvent is recrystallized from acetone to give 1.5 g. of dl-13-ethylgona-4,6-diene- 3,17-dione having a melting point of 177 C.

The compounds of the present invention have utility in experimental and comparative pharmacology due to their cardiotonic activity. 'Cardiotonic activity is determined by the following procedure. A dog is anesthetized with pentobarbital and is artificially (respired. The chest is opened and two small incisions are made in the pericardium overlying the right ventricle. A Brodie-Walton strain gauge measuring isometric myocardial tension is sutured to the right ventricle. Blood pressure is measured from the femoral artery by a transducer. The outputs of the strain gauge and pressure transducer are recorded graphically.

The compounds to be tested are injected intravenously in an appropriate solvent at a rate of 0.2 milligram per kilogram of host body weight per minute (mp.k./min.). Changes in contractile force are generally expressed as a percentage of the control value using epinephrine or quinidine as a standard compound. The value of this method lies in the ability to simultaneously measure changes in blood pressure and changes in the force of contraction of the heart. An active compound increases the myocardial contractile force.

When tested in the foregoing procedure the compounds of the present invention increased the myocardial contractile force from about 40 to over 100 percent.

The final compounds of the invention may be in the natural or d-form, but preferably are in the racemic or dl-form. Most advantageous results may be obtained with the l-form. The steroidal moiety exerts sex hormonal activity in addition to the cardiotonic or digitalis-like effect found for these compounds when the steroidal moiety is in the natural or d-form. The l-form compounds do not have the sex hormonal side efiects. The dl-form has reduced side effects. Compounds designated as the d-forms are the enantiomers corresponding in configuration at (3-13 to that of the natural hormone estrone following a convention approved by Fieser and Fieser in Steroids, p. 336 (1959.). The corresponding enantiomorphs are then designated the l-forms and the racemates the dl-forms.

To obtain the l-form steroids the starting materials are resolved during synthesis. If a resolution stage is not used, the synthetic compounds will be present in the dlform. Resolution of the racemic compounds prior to forming the contemplated bis(amidinohydrazones) can be done by known procedures. One such resolution method is disclosed by Buzby et al. in Jour. Med. Chem., 10, 199 (1967).

When the compounds of this invention are employed as described above, they may be administered alone or in combination with pharmacologically acceptable carriers, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration and standard pharmacological practice. For example, they may be administered orally in the form of tablets or capsules containing such excipients as starch, milk, sugar, certain types of clay and so forth. They may be administered sublingually in the form of troches or lozenges in which the active ingredient is mixed with sugar and corn syrups, and then dehydrated sufficiently to make it suitable for pressing into a solid form. They may be administered orally in the form of solutions which may contain coloring and flavoring agents or they may be injected parenterally, that is intramuscularly, intravenously or subcutaneously. For parenteral administration they may be used in the form of sterile solution containing other solutes, for example, enough saline or glucose to make the solution isotonic.

The dosage of the present therapeutic agents will vary with the form of administration and the particular compound chosen. Furthermore, it will vary with the particular subject under treatment. Generally, treatment is initiated with small dosages substantially less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. It will generally be found that when the composition is administered orally, larger quantities of the active agent will be required to produce the same effect as a smaller quantity given parenterally. In general, the compounds of this invention are most desirably administered at a concentration level that will generally afford effective results without causing any harmful or deleterious side effects.

In order more clearly to disclose the nature of the present invention, specific examples of the practice of the invention are hereinafter given. It should be understood, however, that this is done solely by way of example and is intended neither to delineate the scope of the invention nor limit the ambit of the appended claims.

In the examples all of the temperatures are stated in degrees centigrade, and the following abbreviations are used: gm. for grams, ml. for milliliters, N for normal, mg. for milligrams, and dec. to denote decomposition at the melting point.

EXAMPLE 1 13-ethylgon-4-ene-3 ,17-dione, bis amidinohydrazone) dihydrochloride, hemihydrate To a solution of 2.0 gm. of 13-ethylgon-4-ene-3,17- dione in 20 ml. of methanol is added a solution of 3.0 gm. of aminoguanidine bicarbonate in 25 ml. of .methanol which had been acidified with 5.5 N hydrochloric acid in isopropanol. The reaction mixture is evaporated to about half of its volume on a steambath. The mixture is cooled and ether is aded to incipient turbidity. The resulting precipitate is recrystallized from methanol-ether-acetone to yield 13-ethylgon-4-ene-3,17-di0ne, bis(amidinohydrazone) dihydrochloride, hemihydrate which decomposed at about 333 Analysis.Calcd. for C21H34N8'2HC1'1/2H2O (per cent): C, 52.49; H, 7.76; CI, 14.76; H O, 1.88. Found (percent): C, 52.75; H, 7.65; Cl, 14.80; H O, 1.62.

In the foregoing pharmacological procedure the product was found to increase the myocardial contractile force 82 percent.

Similarly, following the procedure set forth in Example 1, but substituting an equivalent amount of sulfuric'acid in isopropanol for the hydrochloric acid, yields the sulfate salt of l3-ethylgon-4-ene-3,l7-dione, bis(amidinohydrazone).

EXAMPLE 2 1 3-propylgon-4-ene-3, 17 -dione, bis(amidinohydrazone) diacetate Following the procedure described in Example 1, but substituting 13-propylgon-4-ene-3,l7-di0ne for 13-ethylgon-4-ene-3,17-dione and utilizing acetic acid in lieu of hydrochloric acid there is obtained 13-propy1g0n-4-ene- 3,17-dione, bis(amidinohydrazone) diacetate.

EXAMPLE 3 13-ethylgona-4,9-diene-3, l7-dione, bis (amidinohydrazone) dihydrochloride Following the procedure of Example 1, but substituting 13-ethylgona-4,9-diene-3,17-dione for 13-ethylgon-4-ene- 3,17-dione there is obtained 13-ethylgona-4,9 diene-3,l7- dione, bis(amidinohydrazone) dihydrochloride.

In the foregoing pharmacological procedure the product was found to increase the myocardial contractile force 81 percent.

EXAMPLE 4 13-ethylgona-4,6-diene-3,l7-dione, bis(amidinohydrazone) dihydrochloride Following the procedure of Example 1, but substituting 13-ethylgona4,6-diene-3,l7-dione for l3-ethylgon-4-ene- 3,17-dione there is obtained l3-ethylgona-4,6-diene-3,l7- dione, bis(amidinohydrazone) dihydrochloride.

EXAMPLE 5 13-propylgona-4,9-diene-3,17-dione, bis(amidinohydrazone) dihydrochloride Following the procedure of Example 1, but substituting l3 propylgona-4,9-diene-3,17-dione for 13-ethylgon-4- ene-3,l7-dione there is obtained l3-propylgona-4,9-diene- 3,17-dione, bis(amidinohydrazone) dihydrochloride.

EXAMPLE 6 13-ethyl-5 a-gonane-S ,17-dione, bis amidinohydrazone) dihydrochloride, hydrate Following the procedure of Example 1, but substituting l3-ethyl-5a-g0nane-3,l7-dione for 13-ethylgon-4-ene-3,l7- dione, there is obtained 13-ethyl-5ot-gonane-3,17-dione,

bis (amidinohydrazone) dihydrochloride, hydrate having a melting point of 336 (dec.)

Analysis.Calcd. for C H N -2HCl- AH O (percent): C, 52.77; H, 8.12; -N, 23.44; Cl, 14.84. Found (percent): C, 52.59; H, 7.71; N, 23.20; Cl, 14.90.

In the foregoing pharmacological procedure the product was found to increase the myocardial contractile force 85 percent.

EXAMPLE 7 l3-ethylgona-4,9-diene-3,17-dione, bis(amidinohydrazone) dihydrochloride, dihydrate C21H32N8 N, 22.26%. Found: N, 22.15%.

EXAMPLE 8 6-rnethyl-13-ethylgon-4-ene-3,17-dione, bis(amidinohydrazone) dihydrochloride Following the procedure of Example 1, but substituting 6-methyl-13-ethylgon-4-ene-3,l7-dione for 13-ethylgon-4- ene-3,l7-dione there is obtained 6-metl1yl-13-ethylgon-4- ene-3,l7-dione, bis(amidinohydrazone) dihydrochloride.

EXAMPLE 9 13-ethyl-18, 19-dinorpregn-4-ene-3 ,20-dione, bis (amidinohydrazone dihydro chloride To a solution of 0.10 gm. of 13-ethyl-18,19-dinorpregn- 4-ene-3,20-dione in 5.0 ml. of hot methanol is added a solution of 0.15 gm. of aminoguanidine bicarbonate in 5.0 ml. of methanol which is acidified with 5.5 N of hydrochloric acid in isopropanol. The solution is heated on a steam bath for 15 minutes and cooled at to yield 115 mg. of crystalline 13-ethyl-18-19-dinorpregn-4-ene- 3,20-dione, bis(amidinohydrazone) dihydrochloride having a melting point of 338-340 (dec.);

A55; 6.01 and 6.15,u.; A523? 236 mp (e=23,900) and 276 m (e=32,900).

Analysis.Calod. [for C H N '2HCl (percent): C, 55.30; H, 8.07; N, 22.44; Cl, 14.20. Found (percent): C, 54.92; H, 8.36; N, 22.39; Cl, 14.20.

EXAMPLE 10 13-propyl-18,19-dinorpregn-4-ene-3,20-dione, bis- (amidinohydrazone) dihydrochloride Following the procedure of Example 9, but substituting 13-propyl-18,19-dinorpregn-4-ene-3,20-dione for 13-ethyl- 18,19-dinorpregn-4-ene-3,20-dione there is obtained 13- propyl-18,19-dinorpregn-4-ene-3,20-dione, bis(amidinohydrazone) dihydrochloride.

EXAMPLE 11 13-ethyl-16-methoxy-l8,l9-dinorpregn-4-ene-3,20-dione, bis(amidinohydrazone) dihydrochloride Following the procedure of Example 9, but substituting 13-ethyl-16-methoxy-18,19-dinorpregn 4 ene-3,20-dione for 13-ethyl-18,19-dinorpregn-4-ene-3,20-dione there is obtained l3-ethyl-l6-methoxy 18,19 dinorpregn-4-ene- 3,20-dione, bis(amidinohydrazone) dihydrochloride.

EXAMPDE 12 6-methyl-13-ethyl-18,19-dinorpregn-4-ene-3,20-dione, bis amidinohydrazone) dihydrochloride Following the procedure of Example 9, but substituting 6methyl-13 ethyl-l8,19-dinorpregn-4-ene-3,20-di0ne for 13-ethyl-18,l9-dinorpregn-4-ene-3,20-dione there is obtained -6-methyl-13-ethyl-18,19-dinorpregn-4ene 3,20-dione, bis(amidinohydrazone) dihydrochloride.

'EXAMPIJE 13 13-ethyl-1 8,19-dinorpregna-4,6-diene-3 ,20-dione, A bis(amidinohydrazone) dihydrochloride Following the procedure of Example 9, but substituting 13-ethyl-18,19-dinorpregna 4,6 diene-3,20-dione for 13- ethyl-l8,19-dinorpregn-4-ene-3,20-dione there is obtained 13-ethyl-l8,19-dinorpregna-4,6-diene-3,20-dione, bis(amidinohydrazone) dihydrochloride.

EXAMPLE 14 13-ethyl-18,19-dinorpregna-4,9-diene-3,20-dione, bis(amidinohydrazone) dihydrochloride Following the procedure of Example 9, but substituting 13-ethyl-18,19-dinorpregna-4,9-diene-3,20- dione for 13- ethyl-18,19-dinorpregna-4-ene-3,20-dione there is obtained 13-ethyl-18,19-dinorpregna-4,9-diene 3,20 dione, bis(amidinohydrazone) dihydrochloride.

EXAMPLE 15 l3-ethyl-18,19-dinor-5a-pregnane-3,20-dione, bis(amidinohydrazone) dihydrochloride Following the procedure of Example 9, but substituting 13-ethyl-18,19-dinor-5m-pregnane-3,20-dione (for 13-ethyl- 18,19-dinorpregn-4-ene-3,ZO-dione there is obtained 13- ethyl-18,19-dinor-5apregnane-3,20-dione, bis(amidinohydrazone) dihydrochloride.

EXAMPLE 16 13-ethylgona-4,9-diene-3,17-dione, bis(amidinohydrazone), dinitrate To a hot solution of 2.2 gm. of aminoguanidine, nitrate and 60 ml. of methanol is added 1.3 gm. of l3-ethylgona- 4,9-diene-3,l7-dione. The pH is adjusted to 2 and the reaction mixture is stirred at 37 for 3 days. A crystalline product forms and is filtered to yield 1.6 gm. of l3-ethylgona-4,9-diene-3,17-dione, bis(amidinohydrazone), dinitrate having a melting point of 252-257 (dec.).

Analysis.Calcd. for C H N -2HNO (percent): C, 48.26; H, 6.56; N, 26.80. Found (percent): C, 48.09; H, 6.52; N, 25.81.

EXAMPLE 17 l34propylgona-4,9-diene-3,17-dione, bis(amidinohydrazone), dinitrate A hot solution of 740 mg. of aminoguanidine, nitrate and 18 ml. of methanol is treated with 400 mg. of 13- propylgona-4,9-diene-3,17-dione. The reaction is brought to pH 2 with 7% nitric acid and stirred for 4 days at approximately 37 while reducing the volume to 9 ml. by passing nitrogen over the mixture. The resulting mixture is filtered and the precipitate is washed with methanol and acetone to yield 400 mg. of 13-propylgona-4,9-diene- 3,17-dione, bis(amidinohydrazone), dinitrate having a melting point of 238240 (dec.);

KB mati Analysis.-Ca1cd. for C H N -2HN0 (percent): C, 49.24; H, 6.76; N, 26.11. Found (percent): C, 49.03; H, 6.35; N, 26.10.

7 EXAMPLE 1s 13-ethylgona-4,6-diene-3,17-dione, bis(amidinohydrazone) dinitrate A mixture of 1.2 gm. of 13-ethylgona-4,6-diene-3,17- dione, B-amidinohydrazone, nitrate, 70 ml. of methanol, and 1.2 g. of aminoguanidine, nitrate is adjusted to pH 2.5 with 7% nitric acid and refluxed for 2.5 hours. The reaction mixture is then evaporated to 35 ml. and the resulting precipitate filtered. The precipitate is recrystallized with aqueous ethanol, the material filtered off and the clear mother liquor is kept at room temperature for 2 days to yield 13-ethylgona-4,6-diene-3,17-dione, bis- (amidinohydrazone), dinitrate having a melting point of 260 (dec.).

Analysis.Calcd. for C H N -2HNO (percent): C, 48.26; H, 6.50. Found (percent): C, 48.81; H, 6.60.

EXAMPLE 19 13-ethylgona-4,6-diene-3,17-dione, S-amidind hydrazone, nitrate To a warm solution of 2.5 gm. of aminoguanidine nitrate in 70 ml. of methanol is added 1.5 g. of 13-ethylgona-4,6-diene-3,17 -dione. The resulting solution is brought to pH 2 with 7% nitric acid and stirred for 3 days to yield 1.2 g. of 13-ethylgona-4,6-diene-3,17-dione, 3-amidinohydrazone, nitrate having a melting point of 247-250.

Analysis.-Calcd. for C H ON -HNO N, 17.36%. Found: N, 17.03%.

EXAMPLE 2O 13-ethylgona-4,9-diene-3,17-dione, 3 -arnidinohydrazone, hydrochloride To a solution of 2.0 gm. of aminoguanidine bicarbonate in 40 ml. of methanol acidified to pH 1 with isopropanolic hydrochloric acid (8.6 N) is added 2.0 gm. of 13-ethylgona-4,9-diene-3,17-dione in 40 ml. of methanol. The reaction mixture is stirred while passing nitrogen over it to reduce the volume to 40 ml. over a period of 18 hours. The resulting precipitate is filtered to yield 1.2 gm. of 13 ethylgona-4,9-diene-3,l7-dione, 3-amidinohydrazone, hydrochloride having a melting point of 280 (dec.).

Analysis.-Calcd. for C H N O'HCl (percent): C, 63.73; H, 7.75; N, 14.85; Cl, 9.41. Found (percent): C, 63.77; H, 7.35; N, 14.50; Cl, 9.80.

It is understood that the acid addition salts of Examples 1 through 20 can be converted to their free bases by any conventional method.

It is further understood that the D-homo steroids are included within the scope of the invention.

It is also understood that either the tZ I-StCIOldS or specific d or l-isomers may be employed as starting materials with like chemical results.

The terms and expressions which have been employed are used as terms of description and not of limitation, and there is no intention in the use of such terms and expres sions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention claimed.

What is claimed is: I

1. A compound of the formula and the pharmaceutically acceptable acid-addition salts thereof, wherein the 4,5-position is unsaturated, and one O NH 3 wherein R is selected from the group consisting of hydrogen and hydroxy, with the proviso that R is hydroxy and lower alkoxy only when Z is CllHzR. NH

2. A compound according to claim 1 having the structural formula and the pharmaceutically acceptable acid-addition salts thereof, wherein W is an unsaturated linkage between 0-9 and 0-10, and R is an alkyl group of 2 to 8 carbon atoms.

3. A compound according to claim 1 having the structural formula cs N112 and the pharmaceutically acceptable acid-addition salts thereof, wherein W is an unsaturated linkage between C-4 and (3-5; W" is an unsaturated linkage between 0-6 and C-7; and R is an alkyl group of 2 to 8 carbon atoms. 4. A compound according to claim 1 which comprises the pharmaceutically acceptable acid-addition salt of 13- ethylgona-4,9-diene3,17-dione, bis (amidinohydrazone) 5. A compound according to claim 1 which comprises the pharmaceutically acceptable acid-addition salt of 13- ethy1gona-4,6-diene-3,17-dione, bis (amidinohydrazone) 6. A compound according to claim 1 which comprises the pharmaceutically acceptable acid-addition salt of 13- propylgona-4,9-diene-3, l7-dione, bis(amidinohydrazone 7. A compound according to claim 1 which comprises the pharmaceutically acceptable acid-addition salt of 13- ethylgona-4,6-diene-3,17-dione, 3-amidinohydrazone.

8. A compound according to claim 1 which comprises the pharmaceutically acceptable acid-addition salt of 13- ethylgona-4,9-diene-3,l7-dione, 3-amidinohydrazone.

References Cited UNITED STATES PATENTS 5/1966 Schuetz et a1. 260-397 10/1966 Meyer et a1. 260239.5

LEWIS GOTTS, Primary Examiner E. G. LOVE, Assistant Examiner US. Cl. X.R. 

